Each year in the United States, more than 150,000 babies are born with a major congenital malformation. This problem is worse in offspring of women who have poorly controlled type 1 or 2 diabetes during pregnancy; 6%-10% of these babies are born with a major congenital malformation. Based on the National Health and Nutrition Examination Survey conducted during 1988-1994, 1.1% of women 20-39 years of age have type 1 or 2 diabetes, and the incidence of diabetes among women of childbearing age has been increasing over the past four decades. It is projected that the number of women of childbearing age with type 2 diabetes will double by 2010, suggesting that without intervention approximately 8,000 babies will be born each year in the United States with a congenital malformation secondary to type 1 or 2 diabetes.
Human observational studies have demonstrated a strong link between the extent of a mother's glycemic control and the incidence of congenital malformations in her offspring. The putative teratogenic effects of hyperglycemia are supported by studies that demonstrate a reduction in the incidence of birth defects following clinical intervention targeted at achieving euglycemia. When euglycemia is successfully maintained periconceptionally and during the first trimester, the prevalence of malformations is reduced to a level comparable to that of the general population. However, even with excellent compliance and clinical care, euglycemia may be difficult to achieve and maintain. In addition, it is possible that organogenesis can be affected by short periods of hyperglycemia that are not reflected in the averaged values of glycosylated hemoglobin levels, which are used to monitor glucose levels. A further obstacle is that most women with diabetes do not seek pre-pregnancy care and most have unplanned pregnancies. Hence, a very important goal for public health is to develop and implement accessible and affordable intervention strategies to diminish the occurrence of these anomalies.
Both clinical cases and animal studies have clearly demonstrated that the main characteristics of maternal hyperglycemia-associated defects are abnormal organogenesis and underdevelopment. The organ systems most commonly affected include the central nervous, cardiovascular, gastrointestinal, craniofacial, genitourinary, and skeletal systems. Because the heart and the neural tube develop early during embryogenesis, a higher incidence of malformations is often seen in these two organs. In the central nervous system, abnormalities can be categorized as underdevelopment of the midbrain and hindbrain and failure of the neural tube to close at both anterior (rostral) and posterior (caudal) ends of the neural axis. The failure of posterior neural tube closure results in spina bifida, a common birth defect seen in newborns.
Considering the need in the art for compositions and methods for treating a diabetic embryopathy, it is desirable to define an optimal intervention strategy for treating a diabetic embryopathy. The present invention fulfils this long-felt need and desire in the art.